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1. Pharmacokinetics
2
Absorption

2. Drugs are transported across the membranes by:
(a) Passive diffusion and filtration
(b) Specialized transport

3. Passive diffusion
The drug diffuses across the membrane in the
direction of its concentration gradient
(high to low),
the membrane playing no active role in the process.
This is the most important mechanism
for majority o f drugs;
drugs are foreign substances, and
Specialized mechanisms are developed by the body
primarily for normal metabolites.

5. Lipid soluble drugs diffuse by dissolving
in the lipoidal matrix of the membrane,
the rate of transport being proportional
to the lipid : water partition coefficient of the drug.

6. A more lipid-soluble drug attains higher
concentration in the membrane and diffuses quickly.
Also, greater the difference in the
concentration of the drug on the two sides of
the membrane, faster is its diffusion.

7. Influence of pH
Most drugs are weak electrolytes,
i.e. their ionization is pH dependent
(in contrast to strong electrolytes that are
nearly completely ionized at acidic as well as
alkaline pH).

8. The ionization of a weak acid
HA is given by the equation:
pKa is the negative logarithm of acidic dissociation
constant of the weak electrolyte
[A- ] is concentration of ionized drug
[HA] is concentration of unionized drug
A- + H+ = HA

9. If the concentration of ionized drug [A- ] is equal to
concentration of unionized drug [HA], then
since log I is 0, under this condition
pH =pKa
Thus, pKa is numerically equal to the pH at
which the drug is 50% ionized.

10. If pH is increased by I scale, then
log[A-] / [HA] = I
or
[A- ] / [HA] = 10
Similarly, if pH is reduced by I scale, then
[A- ] / [HA] = 1/10

11. Thus, weakly acidic drugs, which form salts with
cations, e.g. sod. phenobarbitone, sod. sulfadiazine,
pot. penicillin-V, etc.
ionize more at alkaline pH and
I scale change in pH causes I0
fold change in ionization.

12. Weakly basic drugs, which form salts with
anions, e.g. atropine sulfate, ephedrine HCI.
chloroquine phosphate, etc.
conversely ionize more at acidic pH.
Ions being lipid insoluble,
do not diffuse and a pH difference across a
membrane can cause differential distribution of
weakly acidic and weakly basic drugs on the
two sides

13. Implications of this consideration are:
(a) Acidic drugs, e.g. aspirin (pKa 3.5) are
largely unionized at acid gastric pH and are
absorbed from stomach,
while bases, e.g. atropine (pKa 10) are
largely ionized and are
absorbed only when they reach the intestines.

14. (b) The unionized form of acidic drugs which
crosses the surface membrane of gastric mucosal
cell, reverts to the ionized form
within the cell (pH 7 .0) and then only
slowly passes to the extracellular fluid.
This is called ion trapping,
i.e. a weak electrolyte crossing a membrane to
encounter a pH from which it is not able to
escape easily.
This may contribute to gastric
mucosal cell damage caused by aspirin.

15. (c) Basic drugs attain higher concentration
intracellularly (pH 7.0 vs 7.4 of plasma).
(d) Acidic drugs are ionized more in alkaline
Urine - do not back diffuse in the kidney
tubules and are excreted faster.
Accordingly, basic drugs are excreted
faster if urine is acidified.
Lipid-soluble nonelectrolytes (e.g. ethanol,
diethyl-ether) readily cross biological membranes
and their transport is pH independent.

16. Filtration
Filtration is passage of drugs through aqueous
pores in the membrane or through para cellular
spaces.

17. This can be accelerated if hydrodynamic
flow of the solvent is occurring under hydrostatic
or osmotic pressure gradient, e.g. across most
capillaries including glomeruli.
Lipid-insoluble drugs cross biological membranes by
filtration if their molecular size is smaller than the
diameter of the pores.
Majority of cells (intestinal mucosa, RBC, etc.) have
very
small pores (4 A) and drugs with MW > 100 or
200 are not able to penetrate.

18. However, capillaries (except those in brain) have
large paracellular spaces (40 A)
and most drugs (even albumin) can filter through
these.
As such, diffusion of drugs across capillaries is
dependent on rate o f blood flow through them
rather than on lipid solubility of the drug or
pH o f the medium.

19. Specialized transport
This can be carrier mediated or
by vesicular transport
(endocytosis, exocytosis).

20. Carrier transport
All cell membranes express
a host of transmembrane proteins
which serve as carriers or transporters
for physiologically important
ions, nutrients, metabolites, transmitters, etc. across
the membrane.
At some sites, certain transporters
also translocate xenobiotics, including drugs
and their metabolites.

21. In contrast to channels, which open for a finite time
and allow passage of specific ions,
transporters combine transiently with their substrate
(ion or organic compound)
Undergo a conformational change
carrying the substrate to the other side of the
membrane
The substrate is dissociated
the transporter returns back to its original
state

23. Carrier transport is specific for the substrate
(or the type of substrate e.g. an organic anion),
Saturable,
competitively inhibited by analogues which utilize the
same transporter,
and is much slower than the flux through channels.

24. Depending on requirement
of energy, carrier transport is of two types:
a. Facilitated diffusion
b. Active transport

25. a . Facilitated diffusion
The transporter, belonging to the super-family of
solute carrier (SLC) transporters,
operates passively without needing energy and
translocate the substrate
in the direction of its electrochemical gradient,
i.e. from higher to lower concentration
It merely facilitates permeation
of a poorly diffusible substrate,
e.g. the entry of glucose into muscle and fat cells
by the

27. b. Active transport
It requires energy,
is inhibited by metabolic poisons,
and transports the solute against
its electrochemical gradient
(low to high),
resulting in selective accumulation of the
substance on one side of the membrane.

28. Drugs related to normal metabolites can utilize the
transport processes meant for these,
e.g. levodopa and methyl dopa are actively absorbed
from the gut by the aromatic amino acid transporter.
In addition, the body has developed some relatively
nonselective transporters, like P-glycoprotein
(P-gp), to deal with xenobiotics.
Active transport can be primary or
secondary depending on the
source of the driving force.

29. i. Primary active transport
Energy is obtained directly by the hydrolysis of ATP.
The transporters belong to the superfamily
of ATP binding cassettee (ABC) transporters
whose intracellular loops have ATPase activity.
They mediate only efflux of the solute from
the cytoplasm, either to extracellular fluid or
into a n intracellular organelle
(endoplasmic reticulum, mitochondria, etc.)

30. Encoded by the multidrug resistance 1 (M DRl) gene
P-gp is the most well known primary active
transporter
expressed in
the intestinal mucosa, renal tubules, bile
canaliculi , choroidal epithelium, astrocyte root
processes
around brain capillaries (the blood-brain barrier),
testicular, and placental micro vessels,
which pumps out many drugs/ metabolites and thus
limit, their intestinal absorption, penetration into
brain,

31. Many xenobiotics which induce or inhibit
P-gp also have a similar effect on the
drug metabolizing isoenzyme CYP3A4,
indicating their synergistic role in
detoxification of xenobiotics.
Other primary active transporters of pharmacological
significance are multidrug resistance associated protein
2
(MRP 2) and breast cancer reistancc protein (BCRP).

32. Secondary active transport
In this type of active transport effected by another set of SLC

34. Metabolic energy
(from hydrolysis of ATP) is spent in maintaining
high transmembrane electrochemical gradient
of the second solute (generally Na+).
The SLC
transporters mediate both uptake and efflux of
drugs and metabolites.

35. The organic anion transporting polypeptide (OATP)
and organic cation transporter (OCT) highly expressed
in liver canaliculi and renal tubules are secondary
active
transporters important in the metabolism and
excretion
of drugs and metabolites (especially glucuronides).
The Na+ ,Cl- dependent neurotransmitter transporters
for norepinephrine, serotonin and dopamine (NET,
SERT and DAT) are active SLC transporters that
are targets for action of drug, like tricyclic

36. As indicated earlier, carrier transport
(both facilitated diffusion and active transport)
Is saturable and follows the Michaelis-Menten
kinetics.
The maximal rate o f transport is
dependent on the density of the transporter
in a particular membrane, and its rate constant
(Km), i.e. the substrate concentration
at which rate of transport is half maximal,
is governed by its affinity for the substrate.

37. Genetic polymorphism can alter both the
density and affinity of the transporter protein
for different substrates and thus affect
the pharmacokinetics of drugs .
Moreover,
tissue specific drug distribution can occur
due to the presence of specific transporters
in certain cells.

38. Vesicular transport
(endocytosis, exocytosis)
Certain substances with very large or impermeable
molecules are transported inside the cell
(endocytosis) or extruded from it (exocytosis)
by enclosing their particles into tiny vesicles.

40. A binding protein located on the membrane
complexes with the substance and initiates
vesicle formation.
The vesicle then
detaches from the membrane and
may remain stored within the cell or
it may release the substance in the cytoplasm, or
it may move to the opposite membrane fuse with it
to release the substance across the cell
(exocytosis).

41. Vesicular transport is applicable to proteins
and other big molecules, and contributes little to
transport of most drugs, barring few like vi t B12
which is absorbed from the gut after binding to
intrinsic factor.
Most hormones (insulin, etc.) and neurotransmitters,
like noradrenaline, are secreted/released from the
cell/nerve ending by exocytosis.

42. Activation of the secretory cell/nerve
ending prompts fusion of the storage vesicle to
the surface membrane followed by extrusion of
its contents into the extracellular space.